Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that causes chronic pain and joint destruction in approximately 1.3 million people in the United States. While drugs to treat RA exist, better treatments strategies are needed to prevent and treat this debilitating disease. As with a variety of autoimmune disorders, there is evidence of an elevated level of tryptophan catabolism in RA patients. This is indicative of activation of the enzyme indoleamine-2,3-dioxygenase (IDO), which initiates the breakdown of tryptophan. IDO is an immune regulatory enzyme that has been implicated in the inflammatory process associated with tumor formation. Because IDO is thought to be immunosuppressive, it has been generally assumed that inhibiting IDO would exacerbate classic autoimmune disorders such as RA. However, data from patients has suggested the opposite, that IDO activity may actually be associated with the development of disease symptoms. Consistent with this, inhibitors of IDO reduce autoantibody titers and alleviate arthritis symptoms in a B cell-mediated mouse model of RA. These data support a role for IDO in exacerbating the disease and further implicate IDO in driving autoreactive B cell responses. This proposal will explore the hypothesis that IDO does not simply promote the general suppression of immune responses, as currently thought, but rather plays a more complex role in modulating inflammation by directing the immune profile of B cell responses. Drug-like inhibitors of IDO and mice that are genetically deficient in IDO, together with the K/BxN mouse model of RA, will be used as tools to determine the mechanism by which IDO inhibition alleviates arthritis development. In this proposal, we will 1) define how the inflammatory features of arthritis induced in mice are inhibited by targeting IDO activity; 2) determine whether IDO-driven B cell activation is unique to the K/BxN model or is a universal phenomenon; and 3) determine whether inhibition of IDO can be used as a co-therapeutic with current RA therapies, to increase their efficacy and reduce their side-effects in the alleviation of arthritis. The long-term goal of this project is to define the mechanism by which IDO modulates the immune response leading to autoimmunity and provide new insights into strategies that can be used to manipulate this pathway to reduce or prevent debilitating disease. If successful, the results from this proposal will suggest that targeting IDO has the exciting potential to lead to a new approach for the prevention and treatment of RA and other autoantibody mediated diseases.